Phosphate-containing copolymers for virulence suppression

Abstract

Phosphate-containing copolymers, medical compositions containing the phosphate-containing copolymers, and methods of suppressing microbial virulence are provided. By suppressing virulence, administration and/or application of the medical compositions can be used to prevent, mitigate, or treat a microbial infection. The phosphate-containing copolymers are prepared by phosphorylating either a random copolymer or a random copolymeric block that contains monomeric units of propylene oxide and glycidol.

What is claimed is: 
     
       1. A phosphate-containing copolymer comprising a first copolymeric unit comprising:
 (a) monomeric units of Formula (I) and 
 
       
         
           
           
               
               
           
         
         (b) monomeric units of Formula (II) or a salt thereof and 
       
       
         
           
           
               
               
           
         
         (c) optional monomeric units of Formula (III) 
       
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, alkyl, aryl, alkaryl, or aralkyl; 
 x is mole percent monomeric units of Formula (I) based on total moles of monomeric units in the first copolymeric unit; 
 y is mole percent monomeric units of Formula (II) based on total moles of monomeric units in the first copolymeric unit; 
 z is mole percent monomeric units of Formula (III) based on total moles of monomeric units in the first copolymeric unit; 
 (x+y+2z) is at least 90 mole percent based on total moles of monomeric units in the first copolymeric unit; 
 100[(y+2z)÷(x+y+2z)] is in a range of 3.5 to 30 percent; and 
 each asterisk (*) denotes a connection site to another monomeric unit or to a terminal group. 
 
     
     
       2. The phosphate-containing copolymer of  claim 1 , wherein 100[(y+2z)÷(x+y+2z)] is in a range of 5 to 30 mole percent based on total moles of monomeric units in the first copolymeric unit. 
     
     
       3. The phosphate-containing copolymer of  claim 1 , wherein the phosphate-containing copolymer is a random copolymer comprising a single first copolymeric unit. 
     
     
       4. The phosphate-containing copolymer of  claim 1 , wherein the phosphate-containing copolymer is a block copolymer comprising at least one block that comprises the first copolymeric unit and at least one second block that is free of phosphate groups and that comprises poly(ethylene oxide), poly(propylene oxide), or a combination thereof. 
     
     
       5. The phosphate-containing copolymer of  claim 4 , wherein the phosphate-containing copolymer is a triblock copolymer comprising (a) two endblocks that are each the first copolymeric unit and (b) a midblock that is free of phosphate groups and that comprises poly(ethylene oxide), poly(propylene oxide), or a combination thereof. 
     
     
       6. The phosphate-containing copolymer of  claim 5 , wherein the midblock is of Formula (IV)
   *—(CH 2 CH 2 O) n —(CH 2 CH(CH 3 )O) q —(CH 2 CH 2 O) m —*   (IV)
 
 
       wherein
 n, q, and m are each an integer that is at least 1; and 
 each asterisk (*) denotes a connection site to another monomeric unit or to a terminal group. 
 
     
     
       7. The phosphate-containing copolymer of  claim 5 , wherein the phosphate-containing copolymer comprises 20 to 70 weight percent midblock based on a total weight of the copolymer. 
     
     
       8. The phosphate-containing copolymer of  claim 1 , wherein the phosphate-containing copolymer contains 0.8 to 6.5 mmoles of phosphate per gram of the phosphate-containing copolymer. 
     
     
       9. The phosphate-containing copolymer of  claim 8 , wherein the phosphate-containing copolymer contains 1 to 3.5 mmoles of phosphate per gram of the phosphate-containing copolymer. 
     
     
       10. The phosphate-containing copolymer of  claim 1 , wherein the phosphate-containing copolymer has a number average molecular weight in a range of 6,000 to 80,000 Daltons. 
     
     
       11. The phosphate-containing copolymer of  claim 10 , wherein the number average molecular weight is in a range of 20,000 to 40,000 Daltons. 
     
     
       12. The phosphate-containing copolymer of  claim 1 , wherein the phosphate-containing copolymer has a solubility in water that is no greater than 200 milligrams per mL at 30 degrees Celsius. 
     
     
       13. A medical composition comprising a phosphate-containing copolymer, wherein the medical composition is suitable for administration to a mammal and wherein the phosphate-containing copolymer comprises a first copolymeric unit comprising:
 (a) monomeric units of Formula (I) and 
 
       
         
           
           
               
               
           
         
         (b) monomeric units of Formula (II) or a salt thereof and 
       
       
         
           
           
               
               
           
         
         (c) optional monomeric units of Formula (III) 
       
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, alkyl, aryl, alkaryl, or aralkyl; 
 x is mole percent monomeric units of Formula (I) based on total moles of monomeric units in the first copolymeric unit; 
 y is mole percent monomeric units of Formula (II) based on total moles of monomeric units in the first copolymeric unit; 
 z is mole percent monomeric units of Formula (III) based on total moles of monomeric units in the first copolymeric unit; 
 (x+y+2z) is at least 90 mole percent based on total moles of monomeric units in the first copolymeric unit; 
 100[(y+2z)÷(x+y+2z)] is in a range of 3.5 to 30 percent; and 
 each asterisk (*) denotes a connection site to another monomeric unit or to a terminal group. 
 
     
     
       14. The medical composition of  claim 13 , wherein the medical composition prevents, mitigates, or treats a microbial infection. 
     
     
       15. The medical composition of  claim 13 , wherein the medical composition is a spray, gel, coating, tablet, or capsule. 
     
     
       16. A method of suppressing microbial virulence, the method comprising administering and/or applying a medical composition, the medical composition comprising a phosphate-containing copolymer, the phosphate-containing copolymer comprising a first copolymeric unit comprising:
 (a) monomeric units of Formula (I) and 
 
       
         
           
           
               
               
           
         
         (b) monomeric units of Formula (II) or a salt thereof and 
       
       
         
           
           
               
               
           
         
         (c) optional monomeric units of Formula (III) 
       
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, alkyl, aryl, alkaryl, or aralkyl; 
 x is mole percent monomeric units of Formula (I) based on total moles of monomeric units in the first copolymeric unit; 
 y is mole percent monomeric units of Formula (II) based on total moles of monomeric units in the first copolymeric unit; 
 z is mole percent monomeric units of Formula (III) based on total moles of monomeric units in the first copolymeric unit; 
 (x+y+2z) is at least 90 mole percent based on total moles of monomeric units in the first copolymeric unit; 
 100[(y+2z)÷(x+y+2z)] is in a range of 3.5 to 30 percent; and 
 each asterisk (*) denotes a connection site to another monomeric unit or to a terminal group. 
 
     
     
       17. The method of  claim 16 , wherein administering and/or applying the medical composition suppresses at least one type of virulence factor selected from pyocyanin, pyoverdine, collagenase, or biofilm. 
     
     
       18. The method of  claim 16 , wherein administering and/or applying the medical composition prevents, mitigates, or treats a microbial infection but does not prevent growth of microbes. 
     
     
       19. The method of  claim 16 , wherein administrating and/or applying the medical composition comprises applying the medical composition to skin, mucosa, internal tissue, wound site, surgical site, implant, or bone. 
     
     
       20. The method of  claim 16 , wherein administrating and/or applying the medical composition reduces or inhibits virulence of gram negative  Pseudomonas aeruginosa , gram positive  Enterococcus faecalis , or gram positive  Staphylococcus aureus.